It has long been known that insulin and glucose play a role in determining glucose uptake by the liver, but recently a third factor, related to portal vein glucose delivery, has been implicated as a physiologic regulator of net hepatic glucose uptake. During feeding the portal glucose level exceeds the arterial glucose concentration and the efficiency with which the liver extracts glucose is enhanced, and the way in which it disposes of the incoming glucose is modified. The hypothesis has been put forward that the portal vein and that this information is compared to input from arterial glucose sensors located elsewhere. We propose to use arterio- venous difference and tracer (radio and stable isotope) techniques to quantitate the metabolic response of the liver in conscious dogs during experiments aimed at furthering our understanding of the physiology of the "portal" signal. The proposal has three main aims. First, we propose to further characterize the effect of the portal signal on the liver. We will assess the time course of the "portal" effect on liver glucose uptake and its effect on the fate of glucose taken up by the liver glucose uptake and its effect on the fate of glucose taken up by the liver (conversion to lactate, oxidation, storage). We will also investigate the interrelationships between insulin, glucagon and the "portal" signal. Second, we propose to test the hypothesis that the "portal" signal is generated when the level of glucose in portal blood is compared to the glucose level in arterial blood reaching the brain. Third, we propose to determine the effect of the "portal" signal in a situation when hormone levels and glucose production are increased (i.e. hypoglycemia) and its role in muscle and liver glycogen repletion following exercise. The proposed experiments will increase our understanding of the role of the liver in postprandial glucose disposal and should yield insight into the role of the nervous system in controlling fuel disposition after feeding.